Amide derivatives of 2,2,3,3-tetramethylcyclopropane carboxylic acid

ABSTRACT

The invention relates to new 2,2,3,3-tetramethylcyclopropane carboxamide derivative compounds, pharmaceutical compositions thereof and uses thereof for treating psychotic disorders, neurodegenerative diseases, epilepsy and pain.

FIELD OF THE INVENTION

The invention relates to new amide derivatives of2,2,3,3-tetramethylcyclopropane carboxylic acid, pharmaceuticalcompositions comprising them as well as uses thereof.

BACKGROUND OF THE INVENTION

Four major antiepileptic drugs (AEDs) are used for the treatment ofepilepsy (epileptic seizures and convulsions): phenytoin, carbamazepine,phenobarbital and valproic acid (VPA). However, about 25% of thepatients do not respond to the current medications. Furthermore, AEDsare administered repetitively as chronic treatment and the adverseeffects associated with antiepileptic therapy are of a major concern.The major established AEDs are associated with some rare but severe sideeffect such as teratogenicity. In addition, all the AEDs have otheradverse effects that limit their use. Valproic acid itself hasconsiderable adverse effects including fatal hepatotoxicity.

One approach to obtain improved antiepileptic agents has been to preparethe primary amide derivatives of valproic acid and its analogs.Valnoctamide (VCD) and propyl-isoproylacetamide (PID) are analogous ofthe amide derivative of valproic acid, valpromide (VPD). They haveimproved anticonvulsant activity when compared to VPA. These amideanalogues of valproic acid have been shown to be non-teratogenic, O.Spiegelstein, M. Bialer, M. Radatz, H. Nau and B. Yagen Chirality,11:645-650 (1999).

Amide derivatives of tetramethylcyclopropane carboxylic acid have alsobeen previously evaluated for their anticonvulsant activity (M. Bialer,S. Hadad, B. Kadry, A. Abdul-Hai, A. Haj-Yehia, J. Sterling, Y. Herzigand B. Yagen Pharm Res. 13:284-289 (1996); J. Sterling, et al. U.S. Pat.No. 5,880,157, issued March. 1999; N. Isoherranen et al, Epilepsy 43:115-126 (2002)). These derivatives had good anticonvulsant activity andsuperior brain penetration than VPA. The N-methyl-tetramethylcyclopropylcarboxamide has a wide spectrum of anticonvulsant activity and isapproximately 10 times more potent than VPA in animal models ofepilepsy. In addition, N-methyl-tetramethylcyclopropane carboxamide andtetramethylcyclopropane carboxamide were not teratogenic in mouse model.

Currently 25% of epileptic patients are not seizure free with existingmedications and thus are considered as therapy resistant or refractoryepileptic patients.

Thus, there is still a substantial need for new anti epileptic andcentral nervous system (CNS) drugs that will be effective in refractoryepileptic patients.

Furthermore, an urgent need still exists in the art for anti epilepticagents with an improved efficacy and a wider margin between the dosewhich is therapeutic and that which is neurotoxic.

Additionally, it would be highly advantageous to have new compoundseffective against pain, psychotic disorders and neurodegenerativediseases.

SUMMARY OF THE INVENTION

According to one aspect of the present invention there is provided a2,2,3,3-tetramethylcyclopropane carboxamide derivative compound offormula I:

including enantiomers, hydrates, solvates and pharmaceuticallyacceptable salts thereof,wherein,

-   -   R₁ is hydrogen or C₁-C₆alkyl group and    -   R₂ is selected from:    -   (a) a member having the structural formula:        —C(═O)—(CH₂)_(n)—NR₃R₄        -   wherein n=0-6, R₃ and R₄ are the same or different and are            independently selected from hydrogen, C₁-C₆alkyl group, an            acyl group having the formula RC(═O)—, wherein R is a            C₁-C₆alkyl group, and a keto group having the formula            RC(═O)R′—, wherein R and R′ are C₁-C₆alkyl groups which may            be the same or different;    -   (b) a C₁-C₆alkyl sulfonamide group;    -   (c) an (N—C₁-C₆alkyl)C₁-C₆alkyl sulfonamide group;    -   (d) an aryl sulfonamide group;    -   (e) a C₁-C₆alkyl aryl sulfonamide group,    -   (f) a thiadiazole sulfonamide group;    -   (g) a C₁-C₆alkyl-thiadiazole sulfonamide group;    -   (h) an (N—C₁-C₆alkyl)aryl sulfonamide group;    -   (i) an (N—C₁-C₆alkyl)C₁-C₆alkyl aryl sulfonamide group;    -   (j) an (N—C₁-C₆alkyl)thiadiazole sulfonamide group;    -   (k) an (N—C₁-C₆alkyl)C₁-C₆alkyl-thiadiazole sulfonamide group;        and    -   (l) a C₁-C₆alkoxy group.

According to another aspect of the present invention there is provided apharmaceutical composition comprising as an active ingredient atherapeutically effective amount of at least one compound as defined inthe present invention and a pharmaceutically acceptable carrier.

According to yet another aspect of the present invention there isprovided a pharmaceutical composition for the treatment of psychoticdisorders, neurodegenerative diseases, epilepsy and pain comprising asan active ingredient a therapeutically effective amount of at least onecompound as defined in the present invention and a pharmaceuticallyacceptable carrier.

According to an additional aspect of the present invention there isprovided use of the compounds as defined in the present invention in thepreparation of a medicament for treating a disease selected from:psychotic disorders, neurodegenerative diseases, epilepsy and pain.

According to yet additional aspect of the present invention there isprovided a method of preventing, treating or ameliorating a medicalcondition selected from psychotic disorders, neurodegenerative diseases,epilepsy and pain, in a mammal in need of such treatment comprisingadministering to the mammal an effective amount of the compound asdefined in the present invention, sufficient to prevent, treat orameliorate the effect of said medical condition.

BRIEF DESCRIPTION TO DRAWINGS

FIG. 1 illustrates the allodynic response presented as percent absoluteresponders in the von frey filaments (VFF) testing.

FIG. 2 illustrates the allodynic response presented as the actualthreshold (absolute) in grams in the VFF testing.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a 2,2,3,3-tetramethylcyclopropanecarboxamide derivative compound of formula I:

including enantiomers, hydrates, solvates and pharmaceuticallyacceptable salts thereof,wherein,

-   -   R₁ is hydrogen or C₁-C₆ alkyl group and    -   R₂ is selected from:    -   (a) a member having the structural formula:        —C(═O)—(CH₂)_(n)—NR₃R₄        -   wherein n=0-6, R₃ and R₄ are the same or different and are            independently selected from hydrogen, C₁-C₆alkyl group, an            acyl group having the formula RC(═O)—, wherein R is a C₁-C₆            alkyl group, and a keto group having the formula RC(═O)R′—,            wherein R and R′ are C₁-C₆ alkyl groups which may be the            same or different;    -   (b) a C₁-C₆alkyl sulfonamide group;    -   (c) an (N—C₁-C₆alkyl)C₁-C₆alkyl sulfonamide group;    -   (d) an aryl sulfonamide group;    -   (e) a C₁-C₆alkyl aryl sulfonamide group,    -   (f) a thiadiazole sulfonamide group;    -   (g) a C₁-C₆alkyl-thiadiazole sulfonamide group;    -   (h) an (N—C₁-C₆alkyl)aryl sulfonamide group;    -   (i) an (N—C₁-C₆alkyl)C₁-C₆alkyl aryl sulfonamide group;    -   (j) an (N—C₁-C₆alkyl)thiadiazole sulfonamide group;    -   (k) an (N—C₁-C₆alkyl)C₁-C₆alkyl-thiadiazole sulfonamide group;        and    -   (l) a C₁-C₆alkoxy group.

It should be noted that the present invention excludes the2,2,3,3-tetramethylcyclopropane carboxamide derivative compoundsdisclosed in references as follows: M. Bialer, S. Hadad, B. Kadry, A.Abdul-Hai, A. Haj-Yehia, J. Sterling, Y. Herzig and B. Yagen Pharm Res.13:284-289 (1996); J. Sterling, et al. U.S. Pat. No. 5,880,157 (issuedMarch. 1999); N. Isoherranen et al, Epilepsy 43: 115-126 (2002); WO03/064374 (PCT/IL02/01050), the disclosures of these references areincorporated herein by reference in their entirety.

As used herein the group —C(═O)— (or —CO—) refers to a carbonyl grouphaving the formula

As used herein the group —S(═O)₂— (or —SO₂—) refers to a sulfonyl grouphaving the formula

As used herein the term “C₁-C₆alkyl” when used alone or in combinationwith other groups refers to a saturated aliphatic hydrocarbon of 1 to 6carbon atoms. The C₁-C₆alkyl may be a straight or a branched alkyl. TheC₁-C₆alkyl group may be for example methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tertiary butyl, sec-butyl, amyl, pentyl, isopentyl,hexyl.

Preferably the alkyl consists of 1-3 carbon atoms and most preferablythe alkyl is a methyl.

The alkyl group may be at the terminal position of the compound or maybe in a non-terminal position of the compound where it is attached at 2different non-terminal carbon atoms to the flanking other groups (inthis case the alkyl refers to alkylene containing from 1 to 6 carbonatoms such as methylene, ethylene, propylene, isopropylene, butylene,isobutylene, tert-butylene, sec-butylene and the like).

For example the R′ of the keto group having the formula RC(═O)R′— refersto a C₁-C₆alkyl group (an alkelene) having for example the structure—(CH₂)_(n)— where n=1-6.

Whenever a numerical range e.g. “1-6” is stated herein, it means thatthe group in this case the alkyl group, may contain 1 carbon atom, 2carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms.

Unless otherwise specified, whenever the term ‘alkyl’ is used in thepresent invention it refers to a C₁-C₆alkyl.

The term “C₁-C₆alkyl sulfonamide” as used herein refers to—(CH₂)_(n)S(═O)₂NH₂, where n=1-6.

The term “N—C₁-C₆alkyl” as used herein refers to the N-monoalkyl orN-dialkyl group of the corresponding compound. Preferably theN—C₁-C₆alkyl is the N-methyl or N-dimethyl group.

The term “(N—C₁-C₆alkyl)C₁-C₆alkyl sulfonamide” as used herein refers to—(CH₂)_(n)S(═O)₂NR₃R₄ where n=1-6, R₃ and R₄ are independently selectedfrom the group consisting of hydrogen and C₁-C₆ alkyl, excluding thecase where R₃═R₄═H.

The term “aryl sulfonamide” as used herein refers to -Aryl-S(═O)₂NH₂.

The term “aryl” in the aryl sulfonamide defined above, refers to anaromatic ring for example a phenyl.

The sulfonamide group may be attached in the meta, ortho or paraposition of the aromatic ring.

The aryl sulfonamide group may be further substituted.

When substituted, the aryl sulfonamide group may be substituted with oneor more, more preferably one, two or three, most preferably one or twosubstituents, preferably halo group.

The term “halo” refers to fluoro, chloro, bromo, or iodo, preferably tochloro.

Preferably the substituted aryl sulfonamide is substituted phenylsulfonamide

Preferably the substituted aryl sulfonamide is chloro-benzenesulfonamideshown below.

The term “(N—C₁-C₆alkyl)aryl sulfonamide” as used herein refers to-Aryl-S(═O)₂NR₃R₄, where R₃ and R₄ are independently selected from thegroup consisting of hydrogen and C₁-C₆ alkyl, excluding the case whereR₃═R₄═H.

Preferably the aryl is a phenyl.

The aryl may be further substituted.

The term “C₁-C₆alkyl aryl sulfonamide” refers to—(CH₂)_(n)-Aryl-S(═O)₂NH₂, where n=1-6, preferably n=1-3 and mostpreferably n=2.

The sulfonamide group may be attached in the meta, ortho or paraposition of the aromatic ring.

Preferably the aryl group is a phenyl.

The aryl of the aryl sulfonamide may be further substituted.

Preferably the C₁-C₆alkyl aryl sulfonamide is ethyl-benzenesulfonamide:

The term “(N—C₁-C₆alkyl)C₁-C₆alkyl aryl sulfonamide” refers to—(CH₂)_(n)-Aryl-S(═O)₂NR₃R₄, where n=1-6, R₃ and R₄ are independentlyselected from the group consisting of hydrogen and C₁-C₆ alkyl,excluding the case where R₃═R₄═H.

Preferably the aryl group is a phenyl.

The aryl of the aryl sulfonamide may be further substituted.

An example for “thiadiazole sulfonamide” is

-   (1,3,4-thiadiazole-2-sulfonamide)

An example for “C₁-C₆alkyl-thiadiazole sulfonamide” is

-   (C₁-C₆-C4-alkyl-Δ²-1,3,4-thiadiazole-2-sulfonamide)

An example for “(N—C₁-C₆alkyl)thiadiazole sulfonamide” is

-   ((N—C₁-C₆alkyl)-1,3,4-thiadiazole-2-sulfonamide)    where R₃ and R₄ are independently selected from the group consisting    of hydrogen and C₁-C₆ alkyl, excluding the case where R₃═R₄═H.

An example for “(N—C₁-C₆alkyl)C₁-C₆alkyl-thiadiazole sulfonamide” is

-   ((N—C₁-C₆alkyl)C₁-C₆-4-alkyl-Δ²-1,3,4-thiadiazole-2-sulfonamide)    where R₃ and R₄ are independently selected from the group consisting    of hydrogen and C₁-C₆ alkyl, excluding the case where R₃═R₄═H.

The term “C₁-C₆alkoxy” as used herein refers to —O—C₁-C₆alkyl whereC₁-C₆alkyl is a straight or branched saturated aliphatic hydrocarbon of1 to 6 carbon atoms.

According to a preferred embodiment of the present invention, R₁ in thederivative compounds of structure formula I is hydrogen.

Further according to a preferred embodiment of the present invention,the alkyl group of R₁ is a straight or branched chain.

Still further according to a preferred embodiment of the presentinvention, any alkyl group or alkoxy group of R₂ is a straight orbranched chain.

For example: the C₁-C₆alkyl group of the C₁-C₆alkyl sulfonamide group;(N—C₁-C₆alkyl)C₁-C₆alkyl sulfonamide group; C₁-C₆alkyl aryl sulfonamidegroup; C₁-C₆alkyl-thiadiazole sulfonamide group; (N—C₁-C₆alkyl)arylsulfonamide group; (N—C₁-C₆alkyl)thiadiazole sulfonamide group;(N—C₁-C₆alkyl)C₁-C₆alkyl-thiadiazole sulfonamide group; and theC₁-C₆alkoxy group may be a straight or branched chain.

Additionally according to a preferred embodiment of the presentinvention, n in the structural formula —C(═O)—(CH₂)_(n)—NR₃R₄ is zero.

In this case where n=0, R₂ is an amide having the structural formula—C(═O)—NR₃R₄ wherein, R₃ and R₄ are the same or different and areindependently selected from hydrogen, C₁-C₆alkyl group, an acyl grouphaving the formula RC(═O)—, wherein R is a C₁-C₆alkyl group, and a ketogroup having the formula RC(═O)R′—, wherein R and R′ are C₁-C₆alkylgroups which may be the same or different.

Further according to a preferred embodiment of the present invention, R₁is hydrogen or C₁-C₆ alkyl group and R₂ is a member having the structureformula: —C(═O)—(CH₂)_(n)—NR₃R₄

wherein n=0, R₃ and R₄ are the same or different and independentlyselected from hydrogen and C₁-C₆alkyl group.

According to this preferred embodiment R₂ is an amide having the formula—C(═O)—NR₃R₄.

Moreover according to a more preferred embodiment of the presentinvention, R₁, R₃ and R₄ are hydrogen. In this case the compound isN-2,2,3,3-tetramethylcyclopropanecarbonyl urea.

Further according to a more preferred embodiment of the presentinvention, at one of R₁, R₃ or R₄ is a methyl.

Examples of compounds where at least one of R₁, R₃ or R₄ is a methyl are1,1-N,N-dimethyl-2,2,3,3-tetramethylcyclopropanecarbonyl urea and1,3-N,N-dimethyl-2,2,3,3-tetramethylcyclopropanecarbonyl urea;

According to additional preferred embodiment of the present invention R₂is an amide group having the structure formula: —C(═O)—NR₃R₄ wherein R₃or R₄ is hydrogen and the other of R₃ or R₄ is selected from an acylgroup having the formula RC(═O)—, wherein R is a C₁-C₆alkyl group, and aketo group having the formula RC(═O)R′—, wherein R and R′ are C₁-C₆alkylgroups which may be the same or different.

More preferably R₃ or R₄ is an acyl group having the formula RC(═O)—wherein R is a C₁-C₆alkyl group.

More preferably R₁ is hydrogen and R₃ or R₄ of the amide group of R₂defined above is hydrogen and the other of R₃ or R₄ is an acyl grouphaving the formula RC(═O)— wherein R is a C₁-C₆alkyl group,

Most preferably the R of the acyl group described above is a methyl (Inthis case the compound is:N-acetyl-2,2,3,3-tetramethylcyclopropanecarbonyl urea).

According to another preferred embodiment of the present invention, theR₂ of the derivative compounds of formula I is C₁-C₆alkoxy group.

According to another more preferred embodiment of the present invention,R₁ is hydrogen and the R₂ is C₁-C₆alkoxy group.

According to another still more preferred embodiment of the presentinvention, the C₁-C₆alkoxy group is methoxy.

Example of a compound where C₁-C₆alkoxy group is methoxy isN-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide.

Additionally according to a preferred embodiment of the presentinvention, R₂ of the derivatives of formula I is thiadiazole sulfonamidegroup.

Moreover according to a more preferred embodiment of the presentinvention, R₁ is hydrogen and the R₂ is thiadiazole sulfonamide group.Example of a preferred compound is5-2,2,3,3-tetramethylcyclopropanecarbonylamido-1,3,4-thiadiazole-2-sulfonamide.

According to an additional preferred embodiment of the presentinvention, R₂ of the derivative compounds of formula I isC₁-C₆alkyl-thiadiazole sulfonamide group.

According to an additional more preferred embodiment of the presentinvention, R₁ is hydrogen and R₂ is C₁-C₆alkyl-thiadiazole sulfonamidegroup.

According to an additional still more preferred embodiment of thepresent invention, R₁ is hydrogen and R₂ is methyl thiadiazolesulfonamide group. A preferred compound according to this embodiment is5-2,2,3,3-tetramethylcyclopropanecarbonylamido-4-methyl-Δ²-1,3,4-thiadiazole-2-sulfonamide.

Further according to a preferred embodiment of the present invention, R₂of formula I is aryl sulfonamide group.

Still further according to a more preferred embodiment of the presentinvention R₁ is hydrogen and R₂ is aryl sulfonamide group.

Still further according to a more preferred embodiment of the presentinvention, the aryl sulfonamide group is a phenyl sulfonamide group.

Example of compounds according to this preferred embodiment are:2,2,3,3-tetramethylcyclopropanecarbonylamidobenzene-o-sulfonamide,2,2,3,3-tetramethylcyclopropanecarbonylamidobenzene-m-sulfonamide, or2,2,3,3-tetramethylcyclopropanecarbonylamidobenzene-p-sulfonamide.

According to a preferred embodiment of the present invention thederivative compounds are selected from:

-   N-2,2,3,3-tetramethylcyclopropanecarbonyl urea;-   1,1-N,N-dimethyl-2,2,3,3-tetramethylcyclopropanecarbonyl urea;-   1,3-N,N-dimethyl-2,2,3,3-tetramethylcyclopropanecarbonyl urea;-   N-acetyl-2,2,3,3-tetramethylcyclopropanecarbonyl urea;-   N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide;-   5-2,2,3,3-tetramethylcyclopropanecarbonylamido-1,3,4-thiadiazole-2-sulfonamide;-   5-2,2,3,3-tetramethylcyclopropanecarbonylamido-4-methyl-Δ²-1,3,4-thiadiazole-2-sulfonamide;-   N-2,2,3,3,-tetramethylcyclopropanecarbonyl-taurinamide;-   2,2,3,3-tetramethylcyclopropanecarbonylamidobenzene-o-sulfonamide;-   2,2,3,3-tetramethylcyclopropanecarbonylamidobenzene-m-sulfonamide;    and-   2,2,3,3-tetramethylcyclopropanecarbonylamidobenzene-p-sulfonamide.

According to a more preferred embodiment of the present invention thederivative is N-2,2,3,3-tetramethylcyclopropanecarbonyl urea.

Some of the compounds of the present invention may posses chiralcenters. Both the racemic mixtures and the specific stereoisomes intheir isolated or essentially isolated forms are within the scope of thepresent invention.

The above compounds are presented in the table below: Compound NumberStructure Chemical Name I

N-2,2,3,3- tetramethylcyclopropane carbonyl urea II

1,1-N,N-dimethyl-2,2,3,3- tetramethylcyclo propanecarbonyl urea III

1,3-N,N-dimethyl-2,2,3,3- tetramethylcyclopropane carbonyl urea IV

N-acetyl-2,2,3,3- tetramethylcyclo propanecarbonyl urea V

N-methoxy-2,2,3,3- tetramethylcyclo propane carboxamide VI

5-(2,2,3,3- tetramethylcyclopropane carbonylamido)-1,3,4-thiadiazole-2-sulfonamide VII

5-(2,2,3,3- tetramethylcyclopropane carbonylamido)-4-methyl-Δ²-1,3,4-thiadiazole-2- sulfonamide VIII

N-2,2,3,3- tetramethylcyclopropane carbonyl-taurinamide IX-XI

2,2,3,3- tetramethylcyclopropanecarbon ylamidobenzene-o-sulfonamide(compound IX) 2,2,3,3- tetramethylcyclopropanecarbon ylamidobenzene-m-sulfonamide (compound X) 2,2,3,3- tetramethylcyclopropanecarbonylamidobenzene-p- sulfonamide; (compound XI)

A compound according to the present invention can be administered to atreated subject (mammal) per se, or in pharmaceutical composition whereit is mixed with suitable pharmaceutically acceptable carriers(excipients).

The invention further provides a pharmaceutical composition comprisingas an active ingredient a therapeutically effective amount of at leastone compound as described in the present invention and apharmaceutically acceptable carrier.

As used herein a “pharmaceutical composition” refers to a preparation ofone or more compounds described herein, with other inert chemicalcomponents such as suitable pharmaceutically acceptable carriers. Thepurpose of a pharmaceutical composition is to facilitate administrationof a compound to a mammal.

As used herein the term “pharmaceutically acceptable carrier” refers toan inert non-toxic carrier or diluent that does not cause significantirritation to a subject (mammal) and does not abrogate the biologicalactivity and properties of the administered compound.

Examples without limitation of carriers are lactose, sucrose, water,organic solvents and polyethyleneglycol.

The carriers may include additional excipients such as binders,disintegrants, lubricants, surface active agents, preservatives andfavoring agents.

Pharmaceutical compositions for use in the context of the presentinvention include compositions wherein the active ingredient iscontained in an amount effective to achieve the intended purpose. Morespecifically, a therapeutically effective amount means an amount of acompound effective to prevent, alleviate or ameliorate one or morecauses, complications or symptoms of a disease of the subject beingtreated.

According to a preferred embodiment of the present invention the routeof administration of the composition is selected from oral, parenteral,inhalation, topical, transdermal, intranasal and rectal.

Additionally according to a preferred embodiment of the presentinvention the parenteral route of administration is selected fromintravenous, intramuscular, intraperitoneal and subcutaneousadministration.

Most preferred is the oral route of administration.

The pharmaceutical composition of the present invention may beformulated as to provide immediate release or sustained release of theactive ingredient from the dosage form after administration to a patientby employing procedures well known in the art.

The final form of the composition includes but not limited to a liquid,a syrup, an elixir, an emulsion, a suspension, drops, a spray, a cream,an ointment, a lotion, a gel, a paste, a powder, a granule, a tablet, acaplet, a pill, a capsule, a suppository, a transdermal patch or aninjection.

The pharmaceutically acceptable carrier selected for preparing thepharmaceutical compositions of the present invention depends on thefinal form of the composition.

Typically, such carriers include additional excipients such as binders,disintegrants, adsorbents, lubricants, wetting agents, buffering agentsand surface active agents.

The pharmaceutical compositions of the present invention are preferablypresent in a unit dosage form. Unit dosage form as used herein refers tophysically discrete units suited as unitary dosages for the mammaliansubject to be treated, such as a tablet, a capsule, or powders in vialsor ampoules, each unit containing a predetermined quantity of the activeingredient calculated to produce the desired therapeutic effect.

Preferably the pharmaceutical composition in a unit dosage formcomprises a therapeutically effective amount of the active ingredient inan amount from 1 mg to 1000 mg, more preferably 10 to 500 mg and mostpreferably 20 to 200 mg.

Oral dosage forms of the present invention suitable for oraladministration may be presented as discrete pharmaceutical unit dosageforms, such as capsules, cachets, soft elastic gelatin capsules,tablets, caplets, or aerosols sprays, each containing a predeterminedamount of the active ingredients, as a powder or granules, or as asolution or a suspension in an aqueous liquid, a non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Dosage formssuch as oil-in-water emulsions typically comprise surfactants such as ananionic surfactant, for example anionic phosphate ester or laurylsulfates, but other types of surfactants such as cationic or nonionicsurfactants may be used in the compositions of the present invention.See generally, Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

For the purpose of preparing a tablet dosage form, variouspharmaceutical carriers which are well-known in this field can be widelyused. As to the examples of carriers, excipients such as lactose, sodiumchloride, glucose, starch, calcium carbonate, kaolin, cellulose,aluminum silicate and the like may be used; the binders may be forexample water, ethanol, propanol, glucose solution, starch solution,gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose,polyvinylpyrrolidone and the like; the disintegrants may be for examplestarch, sodium alginate, sodium laurylsulfate, sodium starch glycolateand the like; the wetting agents may be for example glycerin,surfactants and the like; the adsorbents may be for example starch,lactose, kaolin, bentonite, colloidal silicic acid and the like;lubricants such as talc, strearates, polyethylene glycols and the likecan be used. The tablets preparations can be further shaped into tabletscoated with usual tablet coating, for example sugar coated tablets,gelatin film coated tablets, tablets coated with enteric coating,tablets coated with film coating, or double layer tablets and multiplelayer tablets.

For the purpose of preparing a capsule dosage form, the compounds offormula [I] as the active ingredients are mixed with the above-mentionedvarious carriers and the mixture or granules prepared from the mixturesare placed into rigid gelatin capsules or soft capsules.

For the purpose of preparing a suppository dosage form, various carrierswhich are well-known in this field can be widely used. As to theexamples of carries, polyethylene glycols, cacao butter, higheralcohols, esters of higher alcohols, gelatin, semi-synthesizedglycerides and the like can be mentioned.

For the purpose of preparing an injection dosage form, liquidpreparations, emulsion preparations and suspension preparations aresterilized, further these preparations are preferably isotonic to theblood, and all the diluents which are conventionally used in this fieldcan also be used for example, water, ethyl alcohol, macrogols, propyleneglycol, ethyoxylated isostearyl alcohol, polyoxylated isostearyl alcoholand polyoxyethylenesorbitan fatty acid esters.

Additionally, for the purpose of preparing an isotonic injectionsolutions, an adequate amount of sodium chloride, glucose or glycerinmay be added to the injection preparations, further, usual dissolvingadditives, buffering agents, preservatives and the like may be added.

An example of a pharmaceutical carrier for preparing an injectionemulsion preparation is triglyceride emulsion. An example of anacceptable triglyceride emulsion useful in the intravenous andintraperitoneal administration of the compounds of the present inventionis the triglyceride emulsion commercially distributed under thetradename Intralipid®.

Moreover, if necessary, coloring agents, preservatives, spices, flavors,sweetening agents and others may be added to the pharmaceuticalpreparations of the present invention.

Topical preparations such as creams, ointments, pastes, gels, lotions,transdermal patches, inhalants, sprays, aerosols and the like areformulated by using carriers and exipients which are well known in thefield.

Methods of preparing the compositions of the present invention includethe step of bringing into association a compound of the presentinvention with the pharmaceutical carrier. In general, the compositionsare prepared by uniformly and intimately bringing into association acompound of the present invention with liquid, semi-solid or solidcarriers, and then, if necessary, shaping the product.

The pharmaceutical compositions of the invention may be prepared bymethods of pharmacy well known to those skilled in the art, e.g. bymeans of conventional mixing, dissolving, pulverizing, granulating,compressing, emulsifying, levigating, or lyophilizing processes. Seegenerally, Remington's Pharmaceutical Sciences, 16^(th) ed., MackPublishing Company, Easton, Pa. (1980).

Pharmaceutical compositions for use in accordance with the presentinvention may thus be formulated in conventional manner using one ormore pharmaceutically acceptable carriers comprising excipients andauxiliaries, which facilitate processing of the active compounds intopreparations which, can be used pharmaceutically. The proper formulationis dependent upon the route of administration chosen.

The amount of the active ingredient that may be combined with thepharmaceutical carrier to produce a single dosage form will varydepending upon the mammal treated and the particular mode ofadministration.

For example, a composition intended for oral administration to humansmay vary from about 5% to about 95% w/w of the total composition.

Dosage unit forms will generally contain between 1 to 1000 mg of theactive ingredient, more preferably 10 to 500 mg and most preferably 20to 200 mg.

As used herein the term “treating” includes abrogating, preventing,alleviating, slowing or reversing the progression of a disease, orsubstantially preventing the appearance of clinical symptoms of adisease.

As used herein the term “neurodegenerative disease” refers broadly todisorders or diseases that affect the nervous system and arecharacterized by gradual neuronal loss and/or gradual loss of neuronalfunction, including but are not limited to age-associated memoryimpairment, Parkinson's disease, Alzheimer's disease, Huntington'schorea disease and amyotrophic lateral sclerosis.

The degeneration may also be due to a trauma such as that following headinjury or operation, due to lack of blood supply or oxygen (ischemia orhypoxia) following trauma, stroke or a disease process.

As used herein the term the term “pain” refers to all types of pain.Preferably the term “pain” refers to chronic pain, such as lower backpain; pain due to arthritis, e.g., osteoarthritis; joint pain, e.g.,knee pain or carpal tunnel syndrome; myofascial pain; migraine; andneuropathic pain. The term “pain” further includes acute pain, such aspain associated with muscle strains and sprains; headaches; painassociated with surgery; or pain associated with various forms of tissueinjury, e.g., inflammation, infection, and ischemia.

Most preferably this term concerns neuropathic pain or migraine.

As used herein the term the term “neuropathic pain” refers to any painwhich initial cause was due to injury to the neural tissue whether thepain is experienced at or distal to the site of injury.

As used herein the term the term “migraine” refers to an often familialsymptom complex of periodic attacks of vascular headache, usuallytemporal and unilateral in onset, commonly associated with irritability,nausea, vomiting, constipation or diarrhoea and often photophobia,attacks are preceded by constriction of the cranial arteries, usuallywith resultant prodromal sensory (especially ocular) symptoms andcommence with the vasodilation that follows.

As used herein the term “psychotic disorder” refers to both acute andchronic conditions including schizophrenia, anxiety and relateddisorders (e.g. panic attack), depression and bipolar disorders.

Preferably the term concerns bipolar disorders.

As used herein the term the term “bipolar disease” refers to mooddisorders characterized by a history of manic, mixed, or hypomanicepisodes, usually with concurrent or previous history of one or moremajor depressive episodes, including bipolar I disorder, bipolar IIdisorder, and cyclothymic disorder. Cf. depressive d's. 2. a termsometimes used in the singular to denote either bipolar I d. or bipolarII d., or both.

By a most preferred embodiment the disease is epilepsy.

The present invention additionally relates to the use of the compoundsas defined in the present invention in the preparation of a medicamentfor treating a disease selected from: psychotic disorders,neurodegenerative diseases, epilepsy and pain.

Preferably the psychotic disorder is selected from schizophrenia,anxiety, depression and bipolar disorder.

Preferably the neurodegenerative disease is selected from:age-associated memory impairment, Parkinson's disease, Alzheimerdisease, Hungtinton's chorea disease and amyotropic lateral sclerosis.

In a preferred embodiment the pain is selected from neuropathic pain,chronic pain, headaches and migraine.

As used herein the term “mammal” refers to any member of the classMammalia, including a human.

Preferably, the mammal herein is human.

The present invention additionally provides a method of preventing,treating, or ameliorating a medical condition selected from psychoticdisorders, neurodegenerative diseases, epilepsy and pain, in a mammal inneed of such treatment comprising administering to the mammal aneffective amount of the compound as defined in the present invention,sufficient to prevent, treat or ameliorate the effect of the medicalcondition.

Preferably the psychotic disorder is selected from schizophrenia,anxiety, depression and bipolar disorder.

Preferably the neurodegenerative disease is selected from:age-associated memory impairment, Parkinson's disease, Alzheimerdisease, Hungtinton's chorea disease and amyotropic lateral sclerosis.

In a preferred embodiment the pain is selected from neuropathic pain,chronic pain, headaches and migraine.

According to a preferred embodiment the mammal is a human

Thus, the pharmaceutical compositions of the present invention areuseful for the treatment of psychotic disorders (such as schizophrenia,anxiety, depression or bipolar disorder, preferably bipolar disorder),neurodegenerative diseases (such as age-associated memory impairment,Parkinson's disease, Alzheimer disease, Hungtinton's chorea disease andamyotropic lateral sclerosis), epilepsy and pain (such as neuropathicpain, chronic pain, headaches and migraine).

The treatment may be prophylactic, for preventing the disease fromoccurring such as, for example, for preventing neuropathic painfollowing surgery by administration of the compound of the inventionprior to surgery or for example for prevention of migraines, orepileptic seizures. Alternatively the administration may be performedafter the disease or condition were already established so as toeliminate or decrease at least one of the manifestations of the diseaseor condition.

Preferably, the therapeutically or prophylactically effective amount ofan active ingredient administered orally ranges from 1 mg to 1000 mgdaily, more preferably from 10 mg to 500 mg daily and most preferably 20to 200 mg, either singly or in multiple dosage over 24-hour period. Fororal administration, the therapeutically effective amount of the activeingredient may be several times greater than that for parenteraladministration.

In the practice of the invention the amount of the compound incorporatedin the pharmaceutical composition may vary widely. Factors consideredwhen determining the precise amount are well known to those skilled inthe art. Examples of such factors include, but are not limited to, age,sex and weight of the subject being treated, intended medical use of thecompounds, severity of the disease, the dosage form, route ofadministration being employed and the frequency with which thecomposition is to be administered.

Preparation of the Compounds

The compounds of the present invention may be synthesized according tothe procedures described in: J. Sterling, et al. U.S. Pat. No. 5,880,157and M. Bialer et al, Pharm Res. 13:284-289 (1996). The disclosures ofthese references are incorporated herein by reference in their entirety.

More preferably the compounds of the present invention are synthesizedaccording to the methods outlined below.

The general reaction sequences outlined below are general methods usefulfor preparing the compounds of the present invention and are not meantto be limiting in scope.

The compounds of formula I as defined in the present invention can beprepared according to reaction scheme I. The process preferablycomprises the step of reacting tetramethylcyclopropanecarbonyl chloride(XX) with a suitable amine having the formula (XXI)

wherein R₁ and R₂ are as defined in formula I.Reaction Scheme 1

N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide (compound IV) ofthe present invention may be prepared by reaction scheme I and theprocess described below. Additional non limiting examples of compoundswhich may be synthesized according to reaction scheme I are2,2,3,3-tetramethylcyclopropanecarbonylamidobenzene-(o,m,p)-sulfonamide(compounds IX-XI).

As used herein the term ‘room temperature’ refers to a temperature of20-25° C.

The above process preferably comprises the steps of:

(a) adding tetramethylcyclopropanecarbonyl chloride (XX) dissolved in aninert organic solvent to a stirred solution of a suitable amine havingthe formula (XXI) defined above; (b) stirring the reaction mixture ofstep (a) for about 2 hr to about 24 hr, preferably for 2-4 hr at roomtemperature;

The process further comprises isolating the obtained compounds by meansof the following steps:

(c) evaporating the organic solvent and subsequently adding water; (d)extracting the products obtained in step (c) using a suitable organicextraction medium; (e) a step selected from the group consisting ofdrying, filtering and evaporating the organic medium fraction from step(d); and (f) crystallizing the products using a suitable crystallizingsolvent.

The organic solvent of step (a) may be for example dichloromethane,tetrahydrofuran or mixtures thereof.

The amine solution in step (a) preferably includes an anine(occasionally the amine is present as salt such as for example alkoxylamine hydrochloride) dissolved in organic solvent such as drydichloromethane. To the amine solution in step (a) further added a basicagent such as triethylamine or pyridine. The basic agent is required inorder to increase the yield of the reaction.

Tetramethylcyclopropane carbonyl chloride which is added (drop wise) tothe amine solution during the coupling reaction releases hydrochloricacid. This is captured by the basic agent, otherwise it will neutralizethe amine and will lower the reaction yield.

Occasionally it is preferable not to add a basic agent such as pyridineor triethylamine for example as described in reaction scheme III wherethe urea (or its derivatives) also functions as basic catalyst (basicagent).

The extraction medium of step (d) may be for example ethyl acetate,dichloromethane, chloroform or mixtures thereof, preferably theextraction medium is ethyl acetate.

The organic medium fraction of step (e) may be dried over a drying agentsuch as Na₂SO₄ or MgSO₄.

The crystallizing solvent of step (f) may be for example at least onesuitable organic solvent, preferably a combination of one to threeorganic solvents having different polarities for example a mixture ofethyl acetate:petroleum ether, a mixture of dichloromethane:petroleumether or a mixture of chloroform:hexane. More preferably, thecrystallizing solvent of step (f) is a mixture of ethyl acetate andpetroleum ether.

The compounds of the invention may be prepared according to reactionscheme II.

In step (a) tetramethylcyclopropanecarbonyl chloride (XX) is reactedwith a taurine or its analog having n=1-6 in the formula NH₂(CH₂)_(n)SO₃⁻Na⁺ (XXII) to obtain tetramethylcyclopropanecarbonyl taurine or itsanalog (XXIII);

In step (b) tetramethylcyclopropanecarbonyl taurine or its analog(XXIII) is chlorinated using thionyl chloride (XXIV) to obtaintetramethylcyclopropanecarbonyl taurine chloride or its analog (XXV);and

In step (c) tetramethylcyclopropanecarbonyl taurine chloride or itsanalog (XXV) is reacted with a suitable amine (XXVI) such as NH₃, aC₁-C₆alkyl amine, a C₁-C₆dialkyl amine to obtain compound of formulaXXVII.

The R₃ and R₄ of the amine (XXVI) and amide (XXVII) are the same ordifferent and are independently selected from the group consisting ofhydrogen and C₁-C₆alkyl.

As used herein the term ‘taurine analog’ refers to a straight orbranched —(CH₂)_(n)— alkyl group of the formula NH₂(CH₂)_(n)SO₃ ⁻Na⁺wherein n=1, 3-6.

Taurine refers to the formula NH₂(CH₂)_(n)SO₃ ⁻Na⁺ wherein n=2(NH₂CH₂CH₂SO₃ ⁻Na⁺).

The above process may be used to prepare compounds having the formula I:

wherein R₁ is a hydrogen and R₂ may be for example a C₁-C₆alkylsulfonamide group or an (N—C₁-C₆alkyl)C₁-C₆alkyl sulfonamide group.

Representative compound synthesized by this process is for exampleN-2,2,3,3-tetramethylcyclopropane carbonyl-taurinamide (compound VIII)described in the present invention.

Compounds of formula I wherein R₁ is a C₁-C₆alkyl, may be similarlysynthesized using an N—C₁-C₆alkyl derivative of the taurine or itsanalogue (XXII) in step (a).

Preferably step (a) of the above process (reaction scheme II) comprises:(a) adding tetramethylcyclopropanecarbonyl chloride (XX) to a taurine orits analog (XXII) dissolved in a sodium hydroxide aqueous solution,preferably 5-15%, more preferably 10% sodium hydroxide aqueous solution;and (b) stirring the reaction mixture at room temperature, the stirringmay be conducted for a period of between 3 and 10 hrs, preferably for 5hrs.

The process further comprises isolating the obtained compounds by meansof the following steps:

(c) evaporating the water; (d) extracting the resulting product by asuitable extraction medium such as boiling ethanol; and (e) filteringoff insoluble salts and crystallizing tetramethylcyclopropanecarbonyltaurine or its analog (XXIII) using a suitable solution, the solutionmay be for example a mixture of ethanol and diethyl ether.

Preferably the chlorinating step (b) of the above process (reactionscheme II) comprises:

chlorinating tetramethylcyclopropanecarbonyl taurine or its analog(XXIII) in dry dichloromethane using thionyl chloride (XX).

Preferably step (c) of the above process (reaction scheme II) comprises:

(a) slowly adding the tetramethylcyclopropanecarbonyl taurine chlorideor its analog (XXV) dissolved in dichloromethane to an aqueous solutionof the suitable amine (XXVI); and (b) stirring the reaction mixture atroom temperature;

The process further comprises isolating the obtained compounds by meansof the following steps:

(c) evaporating the organic solvent (dichloromethane); (d) adding waterand extracting the resulting products using a suitable organicextraction medium; (e) a step selected from the group consisting ofdrying, filtering and evaporating the organic fraction; and (f)crystallizing the products using a suitable crystallization solvent.

The amine (XXVI) in the above step (c)(a) may be for example NH₃, aC₁-C₆alkyl amine or a C₁-C₆dialkyl amine.

Preferably the stirring in step (c)(b) is conducted for 2-5 hrs,preferably for about 2 hrs.

The organic extraction medium in step (d) may be for example chloroform.

The organic medium fraction of step (e) may be dried over a drying agentsuch as Na₂SO₄ or MgSO₄.

The crystallization solvent in step (f) may be for example mixture ofchloroform and hexane.

Compounds of the invention can be prepared according to reaction schemeIII.

In reaction scheme III, 2,2,3,3-tetramethylcyclopropanecarbonyl chloride(XXXI) is reacted with urea or urea derivatives having the formula(XXXII)

wherein R₁ is hydrogen or C₁-C₆ alkyl group, R₃ and R₄ are the same ordifferent and are independently selected from hydrogen, C₁-C₆alkylgroup, an acyl group having the formula RC(═O)— wherein R is aC₁-C₆alkyl group, and a keto group having the formula RC(—O)R′— whereinR and R′ are C₁-C₆alkyl groups which may be the same or different.

Representative compound synthesized by this process are for exampleN-2,2,3,3-tetramethylcyclopropanecarbonyl urea (compound I),1,1-N,N-dimethyl-2,2,3,3-tetramethylcyclopropanecarbonyl urea (compoundII) and 1,3-N,N-dimethyl-2,2,3,3-tetramethylcyclopropanecarbonyl urea(compound III).

The process in reaction scheme III is carried our by the followingsteps:

(a) 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (XXXI) dissolved inan inert organic solvent is added to a stirred organic solution of ureaor urea derivative (XXXII); and

(b) the reaction mixture is stirred for additional 2-24 hrs at atemperature of 25-80° C.

The process further includes isolating the obtained compounds by thefollowing steps:

(c) evaporating the organic solvent; (d) dissolving the obtainedproducts in an inert organic solvent and subsequently washing withwater; (e) a step selected from the group consisting of drying,filtering and evaporating the organic fraction from step (d); and

(f) crystallizing the products using a suitable organic solvent.

The inert organic solvent of step (a) may be for example an organicpolar solvent, an organic non-polar solvent or mixtures thereof,preferably the inert organic solvent of step (a) is an organic polarsolvent.

Preferably the organic polar solvent is acetonitrile.

The organic non-polar solvent may be for example benzene ordichloromethane.

The inert organic solvent of step (d) may be for example ethyl acetate,dichloromethane or chloroform.

Preferably the drying in step (e) is performed over a drying agent suchas Na₂SO4, MgSO4 and mixtures thereof.

The organic solvent of step (f) used for crystallization is preferably acombination of one to three organic solvents having differentpolarities.

The combination of the organic solvent may be for example ethylacetate:petroleum ether, dichloromethane:petroleum ether orchloroform:hexane. The ethyl acetate:petroleum ether combination ispreferred.

The above reaction scheme III refers to the synthesis of compounds ofthe present invention wherein R₁ is hydrogen or a C₁-C₆alkyl group andR₂ is a member having the structural formula —C(═O)—(CH₂)_(n)—NR₃R₄wherein n=0, R₃ and R₄ are the same or different and are independentlyselected from hydrogen, C₁-C₆alkyl group, an acyl group having theformula RC(═O)—, wherein R is a C₁-C₆alkyl group, and a keto grouphaving the formula RC(═O)R′—, wherein R and R′ are C₁-C₆alkyl groupswhich may be the same or different.

It is appreciated that compounds wherein R₁ is hydrogen or a C₁-C₆alkyland R₂ is of the structural formula: —C(═O)—(CH₂)_(n)—NR₃R₄ (n=1-6, R₃and R₄ are the same as defined above for n=0), may be similarlysynthesized using a member having the formula R₁HN—(C═O)—(CH₂)_(n)—NR₃R₄instead of the urea or urea derivative having the formulaR₁HN—(C═O)—NR₃R₄ (XXXII) defined above. In the member having the formulaR₁HN—(C═O)—(CH₂)_(n)—NR₃R₄: n=1-6 and R₁, R₃ and R₄ are the same asdefined above for the urea or urea derivative having the formulaR₁HN—(C═O)—NR₃R₄ (XXXII)).

Compounds of the invention can be prepared according to reaction schemeIV and by the method described in Main Group Metal Chemistry 1997, 20,151-156, incorporated herein by reference in its entirety.

In step (a) acetazolamide (XL) is hydrolyzed to obtain an acidic salt of(such as hydrochloride of) 5-amino-1,3,4-thiadiazole-2-sulfonamide (XLI)and acetic acid;

In step (b) the acidic salt of (such as hydrochloride of)5-amino-1,3,4-thiadiazole-2-sulfonamide (XLI) is neutralized till pH 7to form 5-amino-1,3,4-thiadiazole-2-sulfonamide (XLII);

In step (c) TMC-Cl (XLIII) is reacted with5-amino-1,3,4-thiadiazole-2-sulfonamide (XLII) to obtain5-TMCD-1,3,4-thiadiazole-2-sulfonamide (XLIV).

The above process may be used to prepare compounds having the formula I

wherein R₁ is a hydrogen or a C₁-C₆ alkyl and R₂ is a thiadiazolesulfonamide group.

It is appreciated that when R₁ is a C₁-C₆alkyl, the C₁-C₆alkylderivative of acetazolamide (XL) is used in step (a).

Preferably step (a) of the above process comprises

(a) dissolving acetazolamide (XL) in a concentrated acidic solution suchas hydrochloric solution (preferably at a concentration of 20-35% morepreferably 35%) and refluxing (preferably on a water bath, preferably at50-70° C. and more preferably 60° C.);

step (a) further comprises isolating the obtained compound by means ofevaporation of the solvent to obtain a precipitate;

Preferably step (b) of the process of reaction scheme III includesdissolving the precipitate obtained in step (a) (the acidic salt of(such as the hydrochloride of) 5-amino-1,3,4-thiadiazole-2-sulfonamide(XLI)) in water and neutralizing by a basic agent such as NaHCO₃ till pH7 to form 5-amino-1,3,4-thiadiazole-2-sulfonamide (XLII).

Step (b) further includes the step of isolating the obtained product andrecrystallizing using a suitable organic solvent such as methanol.

Preferably step (c) of the above process of reaction scheme IIIcomprises

(a) dissolving TMC-Cl (XLIII) in organic solvent preferably drydichloromethane or dry acetonitrile and adding to5-amino-1,3,4-thiadiazole-2-sulfonamide (XLII) in the presence of abasic agent preferably pyridine;

(b) leaving the reaction mixture for up to 2 hours at 0°-4° C.,preferably under dry conditions;

Step (c) further comprises the isolating the obtained products by meansof the following steps:

(c) evaporating the solvent and subsequently adding water and an organicsolvent preferably ethyl acetate;

(d) separating the organic phase (e.g. ethyl acetate);

(e) evaporation of the organic phase;

(f) recrystallization of the product obtained in step (e) using asuitable organic solvent, preferably a mixture of ethyl acetate:petroleum ether (preferably at a ratio of 1:3).

It is appreciated that in all the processes described above in reactionschemes I-IV and the examples that follows, the organic solvents used inthe reactions (excluding the isolation steps), are preferably dry inertorganic solvents, non limiting examples include dry dichloromethane, dryacetonitrile, or dry tetrahydrofuran.

In the isolation steps the organic solvents may be dry or non-dry.

The following Experimental Details are set forth to aid in anunderstanding of the invention, and are not intended, and should not beconstrued, to limit in any way the invention set forth in the claimsthat follow thereafter.

EXAMPLES

Examples 1-4 describe the general synthesis of some of the compounds ofthe present invention.

Example 1 Synthesis of Compounds Represented by General Formula (I):

R₁ and R₂ are as defined in the present invention.

Representative compound synthesize by this process are for exampleN-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide (compound IV) and2,2,3,3-tetramethylcyclopropanecarbonylamidobenzene-(o,m,p)-sulfonamide(compounds IX-XI).

Tetramethylcyclopropanecarbonyl chloride (TMC-Cl) dissolved in an inertorganic solvent (such as dichloromethane or tetrahydrofuran) was slowlyadded to a stirred reaction mixture with stirring. The reaction mixtureincludes an amine dissolved in an organic solvent such asdichloromethane and a basic agent such as triethylamine or pyridine.Occasionally the amine is present as salt such as for example alkoxylamine hydrochloride. After the addition, the reaction mixture wasstirred for about 2-24 hr, preferably for 2-4 hr at room temperature(20-25° C.). The organic solvent was evaporated, water was added and theproducts were extracted using an organic solvent such as ethyl acetate,dichlorometane or chloroform. The organic fraction was dried over adrying agent such as Na₂SO₄ or MgSO₄, filtered and evaporated. Theproduct was crystallized using at least one suitable organic solvent,preferably a combination of one to three organic solvents havingdifferent polarities for example a mixture of ethyl acetate:petroleumether, dichloromethane:petroleum ether or chloroform:hexane (preferablya mixture of ethyl acetate:petroleum ether) and its chemical structurewas identified by elemental analysis and spectroscopic methods.

Example 2 Synthesis of Compounds Represented by General Formula (I)

wherein R₁ is a hydrogen and R₂ is selected from the group consisting ofa C₁-C₆alkyl sulfonamide group or an (N—C₁-C₆alkyl)C₁-C₆alkylsulfonamide group.

Representative compound synthesized by this process is for exampleN-2,2,3,3-tetramethylcyclopropane carbonyl-taurinamide (compound VIII)described in the present invention.

2,2,3,3-tetramethylcyclopropanecarbonyl taurine (TMC-taurine) issynthesized by adding tetramethylcyclopropanecarbonyl chloride(TMC-chloride) to taurine dissolved in a sodium hydroxide solution,preferably 5-15% NaOH aqueous solution, more preferably 10% NaOH aqueoussolution. The reaction mixture is stirred for 3-10 hrs, preferably for 5hr at room temperature (20-25° C.). The water is evaporated and theproduct is extracted by boiling ethanol. The insoluble salts arefiltered off and TMC-taurine is crystallized using ethanol:diethyl ethersolution. TMC-taurine is chlorinated in dry dichloromethane usingthionyl chloride and the suitable amides (compound XXVII in reactionscheme II) are synthesized by slowly adding of the TMC-taurine chloridein dichloromethane to an aqueous solution of the corresponding amine(compound XXVI in reaction scheme II). After the addition, the reactionmixture is stirred for 2-5 hr, preferably for 2 hr at room temperature(20-25° C.), the organic solvent is evaporated, water is added and theproducts are extracted with a suitable organic medium such aschloroform. The organic fraction is dried using a drying agent such asNa₂SO₄ or MgSO₄, filtered, evaporated and the products are crystallizedusing chloroform:hexane mixtures to get the desirable product. Thechemical structures are identified by elemental analysis andspectroscopic methods.

Example 3

This example describes the synthesis of compounds represented by generalformula (I):

wherein,R₁ is hydrogen or C₁-C₆ alkyl group andR₂ is urea or urea derivatives having the structural formula:—C(═O)—NR₃R₄wherein R₃ and R₄ are the same or different and are independentlyselected from hydrogen, C₁-C₆alkyl group, an acyl group having theformula RC(═O)—, wherein R is a C₁-C₆alkyl group, and a keto grouphaving the formula RC(═O)R′—, wherein R and R′ are C₁-C₆alkyl groupswhich may be the same or different.

2,2,3,3-Tetramethylcyclopropanecarbonyl chloride (TMC-Cl) dissolved indry inert organic solvent, for example a polar organic solvent such asacetonitrile or an non-polar organic solvent such as benzene ordichloromethane (preferably an organic polar solvent such asacetonitrile) was slowly added to a stirred organic solution of urea orurea derivatives (compound XXXII in reaction scheme III). The organicsolution includes an organic solvent for example a polar organic solventsuch as acetonitrile, or an non-polar organic solvent such as benzene ordichloromethane, preferably a polar organic solvent such asacetonitrile.

After addition, the reaction mixture was stirred for additional 2-24 hr,preferably 2-3 hr at a temperature of 25-80° C., preferably at 25-40° C.The organic solvent was evaporated under vacuum, the products weredissolved in an inert organic solvent such as ethyl acetate,dichloromethane or chloroform, preferably ethyl acetate and washed withwater. The organic fraction was dried over a drying agent such as Na₂SO₄or MgSO₄, filtered and evaporated. The obtained oil was crystallizedusing at least one suitable organic solvent, preferably a combination ofone to three organic solvents having different polarities for example amixture of ethyl acetate:petroleum ether, dichloromethane:petroleumether or chloroform:hexane, preferably a mixture of ethyl acetate:petroleum ether and the product was isolated in a crystalline form. Itschemical structure was identified by elemental analysis andspectroscopic methods.

Example 4 Synthesis of5-2,2,3,3-tetramethylcyclopropanecarbonylamido-4-methyl-Δ²-1,3,4-thiadiazole-2-sulfonamide

5-imine-4-methyl-Δ²-1,3,4-thiadiazole-2-sulfomamide (methazol) and abasic agent such as pyridine or triethylamine (preferably triethylamine)are dissolved in an organic solvent preferably anhydrous acetonitrile(or dry dichloromethane). TMC-chloride dissolved in an organic solventpreferably anhydrous acetonitrile (or dry dichlorometane) is slowlyadded to the organic solution including the metazol and the basic agent.The reaction is stirred at room temperature (20° C.-25° C.) for 3-6hours. The solvent is evaporated (e.g. in vacuum). The residue obtainedafter evaporation is dissolved in cold water (preferably at atemperature of about 4° C.) and the precipitate product is filtered andrecrystallized from an organic solvent preferably acetonitrile.(approximate yield 75%).

As used herein methazol refers to

Example 5 Synthesis of N-(2,2,3,3-tetramethylcyclopropanecarbonyl)urea(TMC-Urea) (compound I)

TMC-Urea (compound I) was prepared in a manner analogous to thatdescribed in Example 3 and reaction scheme III.

2,2,3,3-Tetramethylcyclopropanecarbonyl chloride (TMC-Cl) (1.25 g, 8mmole) dissolved in dry boiling acetonitrile was slowly added to stirredacetonitrile solution of urea (1.17 g, 19.5 mmole). After addition, thereaction mixture was stirred for additional 2 hr at 40° C. The organicsolvent was evaporated under vacuum, the products were dissolved in 30ml ethyl acetate and washed with 10 ml water. The organic fraction wasdried over Na₂SO₄, filtered and evaporated under vacuum. The obtainedoil was crystallized using a mixture of solvents, ethyl acetate andpetroleum ether (2:3), and the product (TMC-Urea) was isolated incrystalline form to afford 900 mg (75% yield). Its chemical structurewas identified by elemental analysis and spectroscopic methods.

Results of Chemical Structure and Identification Methods of TMC-Urea:

¹H NMR (CDCl₃; 300 MHz): 8.2 (d, br., 2H), 5.2 (s, br., 1H), 1.6 (s,1H),1.3 (s, 6H), 1.2 (s, 6H) ppm.

MS(m/z): 184 (1.06), 169 (35.64), 126 (38.57), 97 (52.50), 83 (37.22),55 (100).

MP (melting point): 194° C.

Elemental Analysis:

Found (Calculated): C, 58.73%; (58.67%), H, 8.75%; (8.75%), N, 15.50%;(15.21%).

Crystals: White flakes-like crystals

Example 6 Synthesis of1,1-N,N-dimethyl-2,2,3,3-tetramethylcyclopropanecarbonyl urea (compoundII)

The synthesis of1,1-N,N-dimethyl-2,2,3,3,-tetramethylcyclopropanecarbonyl urea wasidentical to the synthesis of TMC-Urea described above (in example 5)with the modification that in this reaction 1,1-dimethyl urea was usedinstead of urea.

The product (1,1-N,N-dimethyl-2,2,3,3,-tetramethylcyclopropanecarbonylurea) was isolated in crystalline form to afford 1.5 g (90% yield). Itschemical structure was identified by elemental analysis andspectroscopic methods.

Results of the chemical structure and identification of1,1-N,N-dimethyl-2,2,3,3,-tetramethylcyclopropanecarbonyl urea

¹H NMR(CDCl₃; 300 MHz): 1.22 (d, J=13.5, 12H), 1.81 (s, 1H), 2.97 (s,6H), 7.56 (br s, 1H).

MS(m/z): 213 (M⁺+1, 3), 125 (32), 109 (41), 96 (70), 82 (68), 55 (100).

MP (melting point): 105° C.

Elemental Analysis:

Found (Calculated): C, 62.17 (62.24); H, 9.52 (9.50), N 13.13 (13.19).

Crystals: White crystals.

Example 7 Synthesis of1,3-N,N-dimethyl-2,2,3,3-tetramethylcyclopropanecarbonyl urea (compoundIII)

The synthesis of1,3-N,N-dimethyl-2,2,3,3-tetramethylcyclopropanecarbonyl urea wasidentical to the synthesis of TMC-Urea described above (in example 5)with the modification that in this reaction 1,3-dimethyl urea was usedinstead of urea.

The product (1,3-N,N-dimethyl-2,2,3,3-tetramethylcyclopropanecarbonylurea) was isolated in crystalline form to afford 1.5 g (90% yield). Itschemical structure was identified by elemental analysis andspectroscopic methods.

Results of the chemical structure and identification of1,3-N,N-dimethyl-2,2,3,3-tetramethylcyclopropanecarbonyl urea

¹H NMR(CDCl₃; 300 MHz): 1.20 (d, J=7.5, 12H), 1.28 (s, 1H), 2.83-2.87(m, 3H), 3.29 (q, J=0.6, 3H), 9.13 (brs, 1H).

MS(m/z): 212 (M⁺, 0.2), 128 (59), 96 (100), 83 (20), 69 (12), 55 (63).

MP (melting point): 55-56° C.

Elemental Analysis:

Found (Calculated): C, 62.11 (62.24); H, 9.43 (9.50); N, 13.24 (13.19).

Crystals: White crystals.

Example 8 Synthesis of N-methoxy-2,2,3,3,-tetramethylcyclopropanecarboxamide (N-methoxy TMCD) (compound V)

N-methoxy TMCD was synthesized in a manner analogous to that describedin example 1 and reaction sheme I.

Tetramethylcyclopropanecarbonyl chloride (TMC-Cl) (4 g; 25 mmol)dissolved in 20 ml of dry dichloromethane was slowly added to a stirredand dry dichloromethane solution of methoxylamine hydrochloride (2.5 g;30 mmol) and triethylamine (6.3 g; 50 mmol). After the addition, thereaction mixture was stirred for 2 hr at room temperature.Dichloromethane was evaporated under vacuum, 10 ml of water was addedand the products were extracted using 30 ml of ethyl acetate. Theorganic fraction was dried over MgSO₄, filtered and evaporated undervacuum. The product was crystallized using 20 ml ethyl acetate and 30 mlpetroleum ether to afford 3 g (75% yield) and its chemical structure wasidentified by elemental analysis and spectroscopic methods.

Results of the chemical structure and identification forN-methoxy-2,2,3,3,-tetramethylcycloproppane carboxamide

¹H NMR(CDCl₃; 300 MHz): 1.18 (s, 6H), 1.28 (s, 7H), 3.74 (s, 3H), 7.84(br s, 1H).

MS(m/z): 171 (M⁺, 0.6), 156 (21), 125 (98), 97(17), 83 (22), 55 (100).

MP (melting point): 78° C.

Elemental Analysis:

Found (Calculated): C, 63.22% (63.13%); H, 9.98% (10.01%); N, 8.24%(8.18%).

Crystals: White wool-like material.

Example 9 Synthesis of5-(tetramethylcyclopropanecarbonylamido)-1,3,4-thiadiazole-2-sulfonamide(compound VI)

Compound VI was synthesized in a manner analogous to that described inreaction scheme IV.

(i) procedure for the synthesis of5-amino-1,3,4-thiadiazole-2-sulfonamide

22.2 gr of acetazolamide, was dissolved in 100 ml concentrated HClsolution (35%) and refluxed on a water bath (60° C.) for two hours.

The solvent was evaporated and the5-amino-1,3,4-thiadiazole-2-sulfonamide was obtained as a whiteprecipitate. This was dissolved in 50 ml of water and neutralized withNaHCO₃ till pH 7. The product was recrystallized from methanol to afford12 g (yield of 54%).

White crystals. M.P. 230-231° C.

(ii) procedure for the synthesis of 5-tetrqmethylcyclopropanecarbonylamido-1,3,4-thiadiazole-2-sulfonamide (compound VI)

4 gr of TMC-Cl dissolved in 52 ml dry dichloromethane were added to 4.5gr of 5-amino-1,3,4-thiadiazole-2-sulfonamide, and 5.2 ml of pyridine ina round bottomed flask. The reaction mixture was held in 4° under dryconditions for 1.5 hrs. The solution was evaporated twice under vacuum,after adding water (50 ml) and the residue was extracted with 150 ml ofethyl acetate. The organic phase was separated and evaporated undervacuum. The product was recrystalized with ethyl acetate:petroleum ether(1:3) to afford 3.2 g (yield 66%).

White crystals. M.P.: 239° C. ¹H NMR (300 MHz, DMSO): 1.189-1.218 (d,12H), 1.543 (s, 1H), 8.265 (br,s 2H).

Anal. (C₁₀H₁₆N₄O₃S₂) C, H, N.

Example 10 Biological Activity

The compounds of the present invention were tested for their ability toprotect against chemically and electrically induced convulsions, in twomodels of epilepsy in mice and rats. The first model, the maximalelectroshock seizure test (MES), is used to show efficacy forantiepileptic agents against partial and generalized seizure typeepilepsy, the common epilepsy among therapy resistant epilepticpatients. The second model, the subcutaneous metrazole test (scMet)measures seizure threshold and is a standard screening procedure to showefficacy for agents against seizure threshold and absence seizures.These models are described in White H S et al, Generalprinciples-Discovery and preclinical development of antiepileptic drugs,in: Antiepileptic Drugs, 5^(th) edition, R H Levy, R H Mattson, B SMeldrum, E Perucca (eds), Lippincott William & Wilkins, Philadelphia2002, pp. 36-48.

The biological activity studies of the present invention were conductedaccording to the protocol described therein (White H S et al, Generalprinciples—Discovery and preclinical development of antiepileptic drugs,in: Antiepileptic Drugs, 5^(th) edition, R H Levy, R H Mattson, B SMeldrum, E Perucca (eds), Lippincott William & Wilkins, Philadelphia2002, pp. 36-48).

As used herein “p.o’ refers to oral administration.

As used herein “ip” refers to intraperitoneal administration.

As used herein “sc” refers to subcutaneous administration.

N-2,2,3,3-tetramethylcyclopropanecarbonyl urea (compound I) showed ananticonvulsant activity in rat-MES model. The ED50 (median effectivedose) in the MES model following oral administration to rats was 29.4mg/kg with a 95% confidence interval (CI) of 17.6 to 47.4 mg/kg. Forcomparison, N-methyl 2,2,3,3-tetramethylcyclopropane carboxamide(M-TMCD) had in rat-MES ED50 of 82 mg/kg with CI of 64 to 103 mg/kg [N.Isoherranen et al, Epilepsia, 43(2): 115-126, 2002] andN-2,2,3,3-tetramethylcyclopropyl carbonyl-glycinamide that had an ED50of 82 mg/kg with CI of 61 to 103 mg/kg (Bialer et al., Pharm. Res. 13(2):284-289, 1996).

Compound I also showed an anticonvulsant activity in rats in the scMettest. The ED50 (rats, p.o.) in the scMet model was 91.8 mg/kg with a 95%confidence interval (CI) of 50-151 mg/kg. For comparison,N-2,2,3,3-tetramethylcyclopropyl carbonyl-glycinamide was in active at adose of 250 mg/kg (ED50>250 mg/kg) [Bialer et al., Pharm. Res. 13(2):284-289, 1996].

Table 1 describes the ED50 biological response of compound I in the MESand scMET test. TABLE 1 ED50 biological response Dose Test (mg/kg)N/F⁽*⁾ MES 10 0/8 MES 20 4/8 MES 40 5/8 MES 80 7/8 scMET 25 1/8 scMET 503/8 scMET 100 3/8 scMET 200 6/8 scMET 400 8/8⁽*⁾N/F represents the fraction of rats responded at a specific dose.

N-2,2,3,3-tetramethylcyclopropanecarbonyl urea (Compound I) showed ananticonvulsant activity in mice-MES model. The ED50 in the MES model inmice following ip administration was 90 mg/kg with a 95% confidenceinterval (CI) of 83 to 96 mg/kg. For comparison, N-methyl2,2,3,3-tetramethylcyclopropane carboxamide (M-TMCD) had in mice-MESED50 of 99 mg/kg with CI of 88 to 109 mg/kg [N. Isoherranen et al,Epilepsia, 43(2): 115-126, 2002] and N-2,2,3,3-tetramethylcyclopropylcarbonyl-glycinamide that had an ED50 of 173 mg/kg with CI values of 149and 202 mg/kg (Bialer et al., Pharm. Res. 13 (2):284-289, 1996).

Compound I also showed an anticonvulsant activity in mice in the scMettest. The ED50 (mice, ip) in the scMet model was 125 mg/kg with a 95%confidence interval (CI) of 93-176 mg/kg.

1,1-N,N-dimethyl-2,2,3,3-tetramethylcyclopropanecarbonyl urea(1,1-N,N-dimethyl TMC Urea) showed an anticonvulsant activity in rat-MESmodel. The ED50 in the MES model following oral administration to ratswas 87 mg/kg with a CI values of 32-211 mg/kg and no neurotoxicity wasshown at doses up to 500 mg/kg.

N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide (compound V)showed an anticonvulsant activity in rat-scMet model. The ED50 in thescMet model following oral administration to rats was 35 mg/kg with CIof 16-54 mg/kg.

Compound V showed an anticonvulsant activity in mice-MES model andMice-scMET model. The ED50 (mice, ip) in the MES model was 115 mg/kgwith CI of 103-126 mg/kg. The ED50 (mice, ip) in the scMet model was 74mg/kg with CI of 64-83 mg/kg.

5-2,2,3,3-tetramethylcyclopropanecarbonylamido-1,3,4-thiadiazole-2-sulfonamide(TMC-thidiazole—Compound VI) showed an anticonvulsant activity inmice-MES model. The ED50 in the MES model in mice following ipadministration was 16 mg/kg with a CI of 14-22 mg/kg.

Neurotoxicity

Neurotoxicity of the claimed agents was assessed in mice (ip.administration) in the rotorod ataxia test and in rats (po.administration) in the gait and stance test which assesses minimalneurotoxicity. The term qauntitating the neurotoxicity is the medianneurological toxic dose (TD50). In some of the species the TD50 wasdetermined to be above a certain level, indicating a lower neurotoxicitythan specified.

The protective index (PI) is defined as the ratio of TD50 and ED50(PI=TD50/ED50). The PI is used to show a useful separation betweenneurotoxicity and antiepileptic activity. The larger the PI, the betterthe separation between neurotoxicity and efficacious doses.

The neurotixicity studies were conducted according to the protocoldescribed in White H S et al, General principles—Discovery andpreclinical development of antiepileptic drugs, in: Antiepileptic Drugs,5^(th) edition, R H Levy, R H Mattson, B S Meldrum, E Perucca (eds),Lippincott William & Wilkins, Philadelphia 2002, pp. 36-48.

The TD50 of compound I (N-2,2,3,3-tetramethylcyclopropanecarbonyl urea(TMC-urea)) was 538 mg/kg following oral administration to rats. Forcomparison N-methyl 2,2,3,3-tetramethylcyclopropane carboxamide (M-TMCD)had an neurotoxic dose (TD50) of 163 mg/kg (CI=138-179 mg/kg) [N.Isoherranen et al, Epilepsy, 43(2): 115-126, 2002]. VPA had a TD50 valueof 280 mg/kg. N-2,2,3,3-tetramethylcyclopropyl carbonyl-glycinamide (TMCglycinamide) had an TD50 of above 500 mg/kg (Bialer et al., Pharm. Res.13 (2):284-289, 1996).

Thus, the protective index or safety of margin TD50/ED50 is 2 forM-TMCD, 0.6 for VPA, >6.1 for TMC glycinamide, and 18.5 for compound I.

The TD50 (mice, ip) of N-Methoxy-2,2,3,3-tetramethylcyclopropanecarboxamide (compound V) was 166 mg/kg with a CI of 152-183 mg/kg.

Taken together, these results suggest that the novel compounds of thepresent invention have unexpected potential as a drug for the treatmentof epilepsy.

The results show that N-2,2,3,3-tetramethylcyclopropanecarbonyl urea andits derivatives such as1,1-N,N-dimethyl-2,2,3,3-tetramethylcyclopropanecarbonyl urea;N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide; and5-2,2,3,3-tetramethylcyclopropanecarbonylamido-1,3,4-thiadiazole-2-sulfonamide;

are preferred because of their high anti-epileptic potency.

N-2,2,3,3-tetramethylcyclopropanecarbonyl urea (Compound I) is morepreferred compared to other cyclopropyl analogues of VPA because of itshigh potency and wide margin of safety.

Example 11

The objective of this study is to asses the antiallodynic activity ofTMC-Urea (compound I) in the rat spinal nerve ligation (SNL) model forneuropathic pain.

Materials and Method

Animals and Experimental Setup

Experiments were performed on male Sprague-Dawley rats (Harlanlaboratories, Jerusalem, Israel) weighing 175-200 g. The mechanicalsensitivity (tactile allodynia) of the foot was quantified by theoccurrence of foot withdrawal in response to normally innocuousmechanical stimuli using nine different von Frey filaments (VFF) rangingfrom 0.6 to 26 g. The rats were placed on a metal mesh floor coveredwith a transparent plastic dome and a period of acclimatization wasallowed prior to testing. VFF were applied from underneath the meshfloor to the plantar surface of the foot. Each trial consisted ofrepeated applications of each of the VFFs in an ascending order for 5times, each for a period of 1 s. If the rat withdrew the foot at least 3times out of 5 at a specific VFF no further ascending filaments weretested and this filament was considered as a withdrawal threshold(response). Mechanical stimulus trials with the series of ascending VFFwere repeated 2 times for a given time point. The repeated measurementswere averaged and taken as the paw withdrawal threshold on a given timepoint.

Rats that did not withdraw the foot to mechanical stimulus (von Freyfilaments) of 15 g and above for 2 consecutive days (−2 and −1) wereincluded in the study. For drug testing, the effect on neuropathic painwas measured 5-6 days following operation. Rats responding to mechanicalstimuli of 10 g or less (in the operated leg) were eligible for thestudy.

Surgical Procedure

The procedure of ligation and cut of the spinal nerves for induction ofneuropathic pain was performed as previously described by Sheen andChung (Sheen, K. and Chung, J. M., Signs of neuropathic pain depend onsignals from injured nerve fibers in a rat model, Brain Research 610:62-68 (1993)). Briefly, under ketamine-xylazine anaesthesia rats wereplaced in a prone position and the left paraspinal muscles wereseparated from spinous processes at the L4-S2 level. Part of the L6transverse process was removed and the L4-L6 spinal nerves wereidentified. The L5-L6 spinal nerves were isolated and tightly ligatedand cut, distal to the dorsal root ganglion and proximal to theformation of the sciatic nerve. Following complete homeostasis the woundwas sutured.

Pharmacologocal Treatments

For all the studies, appropriate amounts of the tested compound weresuspended in 0.5% methylcellulose to a volume of 4 mL/kg body weight.TMC-Urea and methylcellulose (MC, vehicle) were administeredintraperitoneally (i.p) to rats at postoperative days 7, 14 and 21 in adouble blind randomized crossover manner.

Determination of the Median Effective Dose

Rats that obtained threshold of 15 g and above, back to pre-operationbaseline, were regarded free of tactile allodynia. Groups of seven toten animals were administered with increasing doses of TMC-Urea until atleast four points were established between the dose level that did notprotect any of the animals and the dose level that protected 100% of theanimals.

Median effective dose (ED₅₀) and its 95% confidence intervals werecalculated using the pharmacodynamic software package WinNonlin, version4.0.1 (SCI Software, Lexington, Ky., U.S.A.).

Statistical Analysis

Threshold data from VFF testing are presented as actual threshold(absolute) in grams and as percent of absolute responders.

For statistical analyses the nonparametric two-tailed Mann-Whitney U wasused. A p value less than 0.05 was considered significant.

Results

Following the surgical procedure, all rats that entered into this studydisplayed a significant (p<0.05, data not shown) decrease in themechanical stimulus necessary to evoke a brisk withdrawal response ofthe injured hindpaw in response to VFF stimulation, compared topre-surgical response. The contralateral (unoperated) side failed torespond to any filament of 15 g or above.

Effects of TMC-Urea on Tactile Allodynia

Following i.p administration, TMC-Urea decreased tactile allodynia in adose-dependent manner, with a significant reduction in the responseoccurring at 120 to 240 min at 120-240 mg/kg (FIG. 1). The ED₅₀ value,at 120 min post-dose, was 171 mg/kg, CI of 127-215 mg/kg. TMC-Urea atdoses of 120 and 240 mg/kg possessed superiority over vehicle from 30 upto 240 min post-dosing (p≦0.05) with exceptions of 30 min at 120 mg/kg(Table 1). TABLE 1 Allodynic response (number of rats responded/totalnumber of rats) Time Comp 30 60 120 180 240 Total (mg/kg) min min minmin min responders TMC-Urea 20 0/9 0/9 0/9 0/9 0/9 0/9 mg/kg ip 60 0/90/9 0/9 0/9 0/9 0/9 mg/kg ip 120 0/9 1/9 3/9 3/9 3/9 3/9 mg/kg ***** * * ip 180 0/7 1/7 3/7 3/7 3/7 3/7 mg/kg ip 240  0/10  2/10  8/10 8/10  8/10  9/10 mg/kg * *** *** *** *** ip

The statistical analysis was calculated by two-tailed Mann-Whitney test.Significance of threshold from vehicle control at p<0.05, 0.01 and 0.001levels are indicated by single, double and triple asterisks (*),respectively.

FIG. 2 describes the time course of the change in threshold followingadministration of 20, 60, 120, 180 and 240 mg/kg of TMC-urea, i.p. Theexperiments performed with TMC-urea dissolved in the vehicle (methylcellulose) included 5 repetitions using 7-10 rats for each experiment.Significance of threshold from vehicle control at p<0.05, 0.01 and 0.001levels are indicated by single, double and triple asterisks (*),respectively.

While this invention has been shown and described with reference topreferred embodiments thereof, it will be understood by those skilled inthe art that many alternatives, modifications and variations may be madethereto without departing from the spirit and scope of the invention.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated in their entirety by referenceinto the specification, to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated herein by reference.

1. A 2,2,3,3-tetramethylcyclopropane carboxamide derivative compound offormula I:

including enantiomers, hydrates, solvates and pharmaceuticallyacceptable salts thereof, wherein, R₁ is hydrogen or C₁-C₆ alkyl groupand R₂ is selected from: (a) a member having the structural formula:—C(═O)—(CH₂)_(n)—NR₃R₄ wherein n=0-6, R₃ and R₄ are the same ordifferent and are independently selected from hydrogen, C₁-C₆alkylgroup, an acyl group having the formula RC(═O)—, wherein R is aC₁-C₆alkyl group, and a keto group having the formula RC(═O)R′—, whereinR and R′ are C₁-C₆alkyl groups which may be the same or different; (b) aC₁-C₆alkyl sulfonamide group; (c) an (N—C₁-C₆alkyl)C₁-C₆alkylsulfonamide group; (d) an aryl sulfonamide group; (e) a C₁-C₆alkyl arylsulfonamide group; (f) a thiadiazole sulfonamide group; (g) aC₁-C₆alkyl-thiadiazole sulfonamide group; (h) an (N—C₁-C₆alkyl)arylsulfonamide group; (i) an (N—C₁-C₆alkyl)C₁-C₆alkyl aryl sulfonamidegroup; (O) an (N—C₁-C₆alkyl)thiadiazole sulfonamide group; (k) an(N—C—C₆alkyl)C₁-C₆alkyl-thiadiazole sulfonamide group; and (l) aC₁-C₆alkoxy group.
 2. The derivative compound of claim 1 wherein R₁ ishydrogen.
 3. The derivative compound of claim 1 wherein the alkyl groupof R₁ is a straight or branched chain.
 4. The derivative compound ofclaim 1 wherein any alkyl group or alkoxy group of R₂ is a straight orbranched chain.
 5. The derivative compound of claim 1 wherein n in thestructural formula —C(═O)—(CH₂)_(n)—NR₃R₄ is zero.
 6. The derivativecompound of claim 1 wherein R₁ is hydrogen or C₁-C₆ alkyl group and R₂is a member having the structure formula:—C(═O)—(CH₂)_(n)—NR₃R₄ wherein n=0, and R₃ and R₄ are the same ordifferent and are independently selected from hydrogen and C₁-C₆ alkylgroup.
 7. The derivative compound of claim 6 wherein R₁, R₃ and R₄ arehydrogen.
 8. The derivative compound of claim 6 wherein at least one ofsaid R₁, R₃ or R₄ is a methyl.
 9. The derivative compound of claim 1wherein said R₂ is C₁-C₆alkoxy group.
 10. The derivative compound ofclaim 1 wherein said R₁ is hydrogen and said R₂ is C₁-C₆alkoxy group.11. The derivative compound of claim 9 or 10 wherein said C₁-C₆alkoxygroup is methoxy.
 12. The derivative compound of claim 1 wherein R₂ isthiadiazole sulfonamide group.
 13. The derivative compound of claim 1wherein said R₁ is hydrogen and said R₂ is thiadiazole sulfonamidegroup.
 14. The derivative compound of claim 1 wherein said R₂ is arylsulfonamide group.
 15. The derivative compound of claim 1 wherein saidR₁ is hydrogen and said R₂ is aryl sulfonamide group.
 16. The derivativecompound of claims 14 or 15 wherein said aryl sulfonamide group is aphenyl sulfonamide group.
 17. The derivative compound of claim 1, beingselected from: N-2,2,3,3-tetramethylcyclopropanecarbonyl urea;1,1-N,N-dimethyl-2,2,3,3-tetramethylcyclopropanecarbonyl urea;1,3-N,N-dimethyl-2,2,3,3-tetramethylcyclopropanecarbonyl urea;N-acetyl-2,2,3,3-tetramethylcyclopropanecarbonyl urea;N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide;5-2,2,3,3-tetramethylcyclopropanecarbonylamido-1,3,4-thiadiazole-2-sulfonamide;5-2,2,3,3tetramethylcyclopropanecarbonylamido-4-methyl-Δ²-1,3,4-thiadiazole-2-sulfonamide;N-2,2,3,3-tetramethylcyclopropanecarbonyl-taurinamide;2,2,3,3-tetramethylcyclopropanecarbonylamidobenzene-o-sulfonamide;2,2,3,3-tetramethylcyclopropanecarbonylamidobenzene-m-sulfonamide; and2,2,3,3-tetramethylcyclopropanecarbonylamidobenzene-p-sulfonamide.
 18. Apharmaceutical composition comprising as an active ingredient atherapeutically effective amount of at least one compound as defined inany one of claims 1-17 and a pharmaceutically acceptable carrier. 19.The pharmaceutical composition of claim 18 wherein the route ofadministration of said composition is selected from oral, parenteral,inhalation, topical, transdermal, intranasal and rectal.
 20. Thepharmaceutical composition of claim 19 wherein said parenteral route ofadministration is selected from intravenous, intramuscular,intraperitoneal and subcutaneous administration.
 21. A pharmaceuticalcomposition according to claim 18 for the treatment of psychoticdisorders, neurodegenerative diseases, epilepsy and pain.
 22. Use of thecompounds as defined in any of claims 1-17 in the preparation of amedicament for treating a disease selected from: psychotic disorders,neurodegenerative diseases, epilepsy and pain.
 23. The use of claim 22wherein said psychotic disorder is selected from schizophrenia, anxiety,depression and bipolar disorder.
 24. The use of claim 22 wherein saidneurodegenerative disease is selected from: age-associated memoryimpairment, Parkinson's disease, Alzheimer disease, Hungtinton's choreadisease and amyotropic lateral sclerosis.
 25. The use of claim 22wherein said pain is selected from neuropathic pain, chronic pain,headaches and migraine.
 26. A method of preventing, treating orameliorating a medical condition selected from psychotic disorders,neurodegenerative diseases, epilepsy and pain, in a mammal in need ofsuch treatment comprising administering to the mammal an effectiveamount of the compound as defined in any of claims 1-17, sufficient toprevent, treat or ameliorate the effect of said medical condition. 27.The method of claim 26 wherein said psychotic disorder is selected fromschizophrenia, anxiety, depression and bipolar disorder.
 28. The methodof claim 26 wherein said neurodegenerative disease is selected from:age-associated memory impairment, Parkinson's disease, Alzheimerdisease, Hungtinton's chorea disease and amyotropic lateral sclerosis.29. The method of claim 26 wherein said pain is selected fromneuropathic pain, chronic pain, headaches and migraine.
 30. The methodof claim 26 wherein said mammal is a human.